Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.     

Synthesis and Olfactory Evaluation of (+)‐ and (−)‐γ‐Ionone

The synthesis of enantiomerically pure (+)‐ and (−)‐γ‐ionone 3 is reported. The first step in the synthesis is the diastereoisomeric enrichment of 4‐nitrobenzoate derivatives of racemic γ‐ionol 12 . The enantioselective lipase‐mediated kinetic acetylation of γ‐ionol 13b afforded the acetate 14 and the alcohol 15 , which are suitable precursors of the desired products (−)‐ and (+)‐ 3 , respectively. The olfactory evaluation of the γ‐ionone isomers shows a great difference between the two enantiomers both in fragrance response and in detection threshold. The selective reduction of (−)‐ 3 and (+)‐ 3 to the γ‐dihydroionones (−)‐(R)‐ 16 and (+)‐(S)‐ 17 , respectively, allowed us to assign unambiguously the absolute configuration of the γ‐ionones.     

A Practical and Enantiospecific Synthesis of (−)‐(R)‐ and (+)‐(S)‐Piperidin‐3‐ols

A highly enantiospecific, azide‐free synthesis of (?)‐(R)‐ and (+)‐(S)‐piperidin‐3‐ol in excellent yield was developed. The key step of the synthesis involves the enantiospecific ring openings of enantiomerically pure (R)‐ and (S)‐2‐(oxiran‐2‐ylmethyl)‐1H‐isoindole‐1,3(2H)‐diones with the diethyl malonate anion and subsequent decarboxylation.     

Synthesis and Properties of Chiral Pyrazolidines Derived from (+)‐Pulegone

Several enantiomerically pure N(2)‐substituted octahydroindazoles were prepared as bicyclic pyrazolidine derivatives of (+)‐pulegone. Condensation of pulegone with hydrazine delivered a hexahydroindazole intermediate, which underwent N(2)‐substitution with various electrophiles (alkyl halides, acyl chlorides, phenyl isocyanate). The resulting N(2)‐substituted hexahydroindazoles could be reduced with LiBEt₃H in THF to the target compounds. In addition, a N(2)‐thiobenzoyl and some N(2)‐carbamoyl derivatives as well as a N(1)‐substituted octahydroindazole were synthesized. The compounds showed medium activity as iminium ion catalysts promoting quantitatively the Michael addition of nitroethane to cinnamaldehyde in up to 82 % ee for the resulting syn‐diastereoisomer and 78 % ee for the anti‐diastereoisomer. Unexpectedly, the N(2)‐acyloctahydroindazoles were readily oxidized under aerobic conditions. Moreover, it was shown that an oxidation of methyl phenyl sulfide to the corresponding sulfoxide is promoted by an N(2)‐acyloctahydroindazole in deuterochloroform as solvent. It is proposed that the oxidation of N(2)‐acyloctahydroindazoles proceeds by in situ generation of hydrogen peroxide, which in turn can act as an oxidant.     

An Efficient Synthesis of Optically Active trans‐(3R,4R)‐3‐Acetoxy‐4‐aryl‐1‐(chrysen‐6‐yl)azetidin‐2‐ones Using (+)‐Car‐3‐ene as a Chiral Auxiliary

An efficient enantioselective synthesis of 3‐acetoxy trans‐β‐lactams 7a and 7b via [2+2] cycloaddition reactions of imines 4a and 4b , derived from a polycyclic aromatic amine and bicyclic chiral acid obtained from (+)‐car‐3‐ene, is described. The cycloaddition was found to be highly enantioselective, producing only trans‐(3R,4R)‐N‐azetidin‐2‐one in very good yields. This is the first report of the synthesis of enantiomerically pure trans‐β‐lactams 7a and 7b with a polycyclic aromatic substituent at N(1) of the azetidin ring.     

Short and Divergent Total Synthesis of (+)‐Machaeriol B, (+)‐Machaeriol D, (+)‐Δ8‐THC,and Analogues

Short and highly efficient stereoselective syntheses provide machaeriols and cannabinoids in a divergent approach starting from a common precursor, commercially available (S)‐perillic acid. Key features of the novel strategy are a stereospecific palladium‐catalyzed decarboxylative arylation and a one‐pot sequence comprising a stereoselective hydroboration followed by oxidation or reduction of the corresponding intermediary boranes. The divergent approach is convincingly demonstrated by the five‐step syntheses of (+)‐machaeriol B, (+)‐machaeriol D, and related analogues, and the four‐step synthesis of (+)‐Δ⁸‐THC and an analogue.     

The Biomimetic Synthesis and First Characterization of the (+)‐ and (−)‐Isocentrolobines, 2,6‐cis‐ and 2,6‐trans‐Disubstituted Tetrahydro‐2H‐pyrans

The four stereoisomers of the novel title compounds were prepared by oxidative cyclization of their enantiomerically pure diarylheptanoid precursors by means of the straightforward biomimetic approach presented in the preceding article. The isocentrolobines are the methoxy regioisomers of the natural (+)‐ and (−)‐centrolobines and were characterized for the first time. The synthetic procedure established the absolute configurations and the unambiguous correlation with the chiroptical data. The spectroscopic and the chiroptical data of the isocentrolobines are highly similar to those of the natural products. The single diagnostic parameter that would allow a immediate assignment in the presence of only one of the isomers is the higher melting point (ca. 50°) of the cis‐configured isocentrolobines.     

Stereoselective Access to γ‐Nitro Carboxylates,Precursors for Highly Functionalized γ‐Lactams

A straightforward synthesis of the enantiomerically pure nitro derivatives 31 and epi‐ 32 , which are particularly useful intermediates for the synthesis of highly functionalized γ‐lactams, is presented. (+)‐(R)‐3‐Hydroxy‐3‐phenylpropanoic acid ( 20 ) and its ethyl ester 25 were prepared from (+)‐L ‐mandelic acid ( 21 ). Condensation of 20 with pivalaldehyde furnished the novel enantiomerically pure 1,3‐dioxan‐4‐one 17 , the absolute configuration of which was established by X‐ray crystal‐structure analysis. Treating the lithium enolate of 17 with the nitro alkene 18 led, in a Michael‐type addition, to a 1 : 1 mixture of two diastereoisomeric products. The stereocontrol of the addition was limited to the novel stereogenic center next to the lactone function. When the lithium enolate of 25 was treated with 18 , the same selectivity was observed but with a lower chemical yield. Very facile separation of the isomers was achieved later in the synthetic sequence, when one isomer cyclized selectively to the nitro lactone 31 , while the other one was isolated as hydroxy ester epi‐ 32 . The relative configuration of racemic epi‐ 32 could be established by X‐ray crystal‐structure analysis.     

Synthetic Studies Toward (+)‐Spongidepsin

A convergent enantiomerically controlled synthetic effort toward (+)‐spongidepsin is reported. The synthesis benefits from the use of readily available and inexpensive starting materials like D ‐mannitol and (?)‐β‐citronellene. Key transformations include Evans asymmetric methylation, Mitsunobu esterification, (1H‐benzotriazol‐1‐yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)‐mediated amide formation for the preparation of a fully functionalized acyclic precursor, and ring‐closing metathesis (RCM).     

Synthesis of (−)‐Erythrodiene and (+)‐7‐Epispirojatamol via Intramolecular Pd‐Catalyzed Allylzincation

Two spirobicyclic sesquiterpenoids, (−)‐erythrodiene ( 1 ) and (+)‐7‐epispirojatamol ( 30 ), were synthesized in enantiomerically pure form via an intramolecular allylzincation process. The allylzinc species were formed in the presence of Et₂Zn via transmetallation of a catalytically generated allylpalladium intermediate. Several Pd catalysts were tested for this transformation, and [Pd(OAc)₂]/Bu₃P (1 equiv.) was found to be, by far, the most effective. Whereas the preparation of 1 involved allylzincation of a tethered terminal olefin, 30 was formed via a novel intramolecular allyl zincation of a methyl ketone. Both reactions showed the same stereochemical preference, yielding the spirobicyclic products in 95 : 5 and 4 : 1 diastereoisomer ratios, respectively.     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C?H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C−H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

A Divergent Approach to the Marine Diterpenoids (+)‐Dictyoxetane and (+)‐Dolabellane V

We present a full account of the development of a strategy that culminated in the first total syntheses of the unique oxetane‐containing natural product (+)‐dictyoxetane and the macrocyclic diterpene (+)‐dolabellane V. Our retrosynthetic planning was guided by both classical and nonconventional strategies to construct the oxetane, which is embedded in an unprecedented 2,7‐dioxatricyclo[4.2.1.0^3,8]nonane ring system. Highlights of the successful approach include highly diastereoselective carbonyl addition reactions to assemble the full carbon skeleton, a Grob fragmentation to construct the 11‐membered macrocycle of (+)‐dolabellane V, and a bioinspired 4‐exo‐tet, 5‐exo‐trig cyclization sequence to form the complex dioxatricyclic framework of (+)‐dictyoxetane. Furthermore, an unprecedented strain‐releasing type I dyotropic rearrangement of an epoxide‐oxetane substrate was developed.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

(R)‐4‐(4‐Aminophenyl)‐2,2,4‐trimethylchroman and (S)‐4‐(4‐aminophenyl)‐2,2,4‐trimethylthiachroman

The title compounds, C₁₈H₂₁NO and C₁₈H₂₁NS, in their enantiomerically pure forms are isostructural with the enantiomerically pure 4‐(4‐hydroxyphenyl)‐2,2,4‐trimethylchroman and 4‐(2,4‐dihydroxyphenyl)‐2,2,4‐trimethylchroman analogues and form extended linear chains via N—H...O or N—H...S hydrogen bonding along the [100] direction. The absolute configuration for both compounds was determined by anomalous dispersion methods with reference to both the Flack parameter and, for the light‐atom compound, Bayesian statistics on Bijvoet differences.     

A Facile Solid‐Phase Synthesis of (+)‐(S)‐Clopidogrel

Enantiomerically pure (+)‐(S)‐clopidogrel was prepared by solid‐phase synthesis using the commercially available Wang resin. This method offers mild reaction conditions and provides the (+)‐(S)‐clopidogrel in overall 52% yield over six steps and with optical purity of 98.0% ee.     

Enantioselective Total Synthesis of (+)‐Jungermatrobrunin A

A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A ( 1 ), which features a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps by making use of a late‐stage visible‐light‐mediated Schenck ene reaction of (?)‐1α,6α‐diacetoxyjungermannenone C ( 2 ). Along the way, a UV‐light‐induced bicyclo[3.2.1]octene ring rearrangement afforded (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one ( 4 ). These divergent photo‐induced skeletal rearrangements support a possible biogenetic relationship between (+)‐ 1 , (?)‐ 2 , and (+)‐ 4 .     

Diastereo‐ and Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 3‐(ω′‐Alkenyl)‐ and 3‐(ω′‐Alkenyloxy)‐Substituted 5,6‐Dihydro‐1H‐pyridin‐2‐ones

3‐(ω′‐Alkenyl)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 2 – 4 were prepared as photocycloaddition precursors either by cross‐coupling from 3‐iodo‐5,6‐dihydro‐1H‐pyridin‐2‐one ( 8 ) or—more favorably—from the corresponding α‐(ω′‐alkenyl)‐substituted δ‐valerolactams 9 – 11 by a selenylation/elimination sequence (56–62 % overall yield). 3‐(ω′‐Alkenyloxy)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 5 and 6 were accessible in 43 and 37 % overall yield from 3‐diazopiperidin‐2‐one ( 15 ) by an α,α‐chloroselenylation reaction at the 3‐position followed by nucleophilic displacement of a chloride ion with an ω‐alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ=254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5 , tethered by a two‐atom chain, exclusively delivered the respective crossed products 19 and 20 , and substrates 3 , 5 , and 6 , tethered by longer chains, gave the straight products 21 – 23 . The completely regio‐ and diastereoselective photocycloaddition reactions proceeded in 63–83 % yield. Irradiation in the presence of the chiral templates (?)‐ 1 and (+)‐ 31 at ?75 °C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85 % ee. Truncated template rac‐ 31 was prepared as a noranalogue of the well‐established template 1 in eight steps and 56 % yield from the Kemp triacid ( 24 ). Subsequent resolution delivered the enantiomerically pure templates (?)‐ 31 and (+)‐ 31 . The outcome of the reactions is compared to the results achieved with 4‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones and quinolones.     

Highly Diastereoselective Total Syntheses of (+)‐7‐Epigoniodiol, (−)‐8‐Epigoniodiol,and (+)‐9‐Deoxygoniopypyrone

An expedient concise total synthesis of (+)‐7‐epigoniodiol, (?)‐8‐epigoniodiol, and (+)‐9‐deoxygoniopypyrone is accomplished. The key transformations include a catalytic hydroxylation and base‐mediated N‐(acetyl)oxazolidinone addition reactions, which could set the consecutive OH motif that is either syn,syn or syn,anti with high diastereoselectivity. Moreover, this approach envisioned to facilitate the synthesis of other representatives of the family with structural and stereochemical variation.     

Enzyme‐Mediated Syntheses of the Enantiomers of γ‐Irones

An enzymatic approach to the synthesis of all the possible stereoisomers of (E) and (Z), cis and trans‐γ‐irones in enantiomerically pure form from commercial Irone Alpha^® is described. A very efficient resolution of racemic trans‐γ‐irone, affording both the enantiomers in high ee and chemical purity, is also presented. Olfactory evaluation of (+)‐ and (−)‐ 3b and full configuration assignment of the irone isomers contained in samples of Italian iris oil are reported.